1. Field of the Invention
The invention relates to the field of pharmacology and, in particular, to sustained-release particles for parenteral administration of active pharmaceutical ingredients. The invention also relates to methods for preparing such particles containing an active pharmaceutical ingredient.
2. Description of the Related Art
In certain situations, it is desired that a pharmaceutical agent be administered in a sustained-release formulation, often to achieve a nearly constant or pseudo-zero-order release rate over a significant period of time and to reduce the problems associated with previous administration methods. By way of non-limiting example, such problems include poor bioavailability, first pass metabolism, non-compliance or non-adherence to therapy, and reducing the opportunity for sequestering drug tablets for illegal use. For example, the production and use of pharmaceutical preparations including larger drug particles to sustain delivery have been described in the art for certain antibiotics, insulin, and steroids (see, e.g., Ansel, Allen and Popovich, eds., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 1999; Gennaro ed., Remington: The Science and Practice of Pharmacy, 19th Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 1995)).
Most sustained release systems employ a finely milled or micronized preparation of the active pharmaceutical ingredient as a starting point in the formulations. The release of the active pharmaceutical ingredient into the body is then controlled using matrices, membranes or other inactive ingredients or devices. Examples of methods and devices known in the art for sustained release formulations include liposomes, bioerodable matrices (e.g., PLA/PGLA matrices), drug-permeable implants (e.g., U.S. Pat. No. 3,993,073 to Zaffaroni), implants with drug-permeable and drug-impermeable membranes (e.g., U.S. Pat. No. 5,378,475 to Smith et al.), and osmotic drug delivery systems (e.g., U.S. Pat. No. 4,439,196 to Higuchi).
Penicillin G and V have been formulated as a sustained release injection by complexing the penicillin molecule with procaine or with benzathine. Suspensions of crystals of benzathine and procaine penicillin can be useful in the treatment of rheumatic fever and other infections. Typically, therapeutic levels of these antibiotics can be sustained for 14-28 days after a single IM injection (Cadorniga et al. (1991), Eur. J. Drug Metab. Pharmacokinet. 3:379-84; Kaplan et al. (1989), J. Pediatr. 115(1):146-50; U.S. Pat. No. 2,627,491; U.S. Pat. No. 2,515,898). These formulations are based on large particles of the insoluble penicillin salts which dissolve slowly over approximately two weeks. However, because delivery from these sustained release formulations is first-order the drug levels achieved at the end of the treatment period are significantly less than those achieved at the beginning of treatment.
An effort has also been made using matrix technology to achieve a sustained release injectable formulation for the drug risperidone which lasts several weeks. In addition there are sustained release preparations for other antipsychotic drugs, including decanoate esters of perphenazine and haloperidol.
There remains, however, a need in the art for improved methods for the parenterally administrable sustained-release formulations of active pharmaceutical ingredients.